Yesterday we learned that the Memorial Sloan Kettering Cancer Center (MSKCC) and corporate partner Juno had stopped enrolling patients into 5 clinical trials of their chimeric antigen receptor (CAR) T cell therapies. Details are spare at this point, but unexpectedly, the cause of the clinical stop was severe cytokine release syndrome (CRS). I say ‘unexpectedly’ because it was just last month that MSKCC released an update on their ability to detect CRS early enough to initiate aggressive treatment. We commented on this update in a recent post on the CAR 19-28z technology.
According to the MSKCC update given in February, they had developed “guidelines for managing the side effects of cell therapy” including CRS, and “diagnostic criteria” for identifying at-risk patients using clinical lab tests. These tests were for a panel of cytokines and for C-reactive protein (CRP). To be fair these comments were made in reference to work ongoing in acute lymphocytic leukemia (ALL), but it was clear that the clinicians felt they were broadly applicable. It seems now that these comments were premature.
This is a critical issue in the CAR technology field, potentially holding back not just MSKCC/Juno but similar work from U Penn/Novartis and NCI and partners working with Kite Pharma. The syndrome characterized as CRS is a consequence of the massive immune response to the tumor, which is a designed consequence of the CAR technology. CAR-modified T cells are potent cytotoxic agents, and are designed to recruit unmodified T cells to the cause (the so-called bystander effect). This result is the triggering of the acute phase response, and then an outpouring of cytotoxic compounds, pro-inflammatory cytokines, and effector proteins. When allowed to proceed unchecked, the response begins to engulf normal cells and tissues, causing additional cell death, organ damage, and in the most severe cases, death.
The reality is that clinical responses leading to CRS seem to have caught MSKCC/Juno flat footed in at least one clinical trial of Non-Hodgkin’s Lymphoma (NHL) – we note here that stopping 5 trials does not mean that CRS was seen in all 5, but they are related by clinical indication, so it is an obvious precautionary step to take.
What will happen next we cannot know yet, as we have not yet heard the necessary detail. At the very least the MSKCC/Juno NHL programs are in for careful scrutiny. This will impact the clinical development of the technology and slow access for patients. The patients affected are those who are the most in need, nonetheless, the caution is warranted. More broadly, this unexpected turn of events may encourage us to look again at more established therapeutics for NHL, including small targeted molecule drugs, cytotoxic antibodies, antibody-drug conjugates (ADCs) and bispecifics, and of course, combinations of those therapies with one another or with current chemotherapeutics.
And this just in: In the immune checkpoint space we have just learned this morning of the potential for unexpected immune toxicity after long term treatment. Thankfully this appears to be very rare but this too will bear watching.